Catalytic enantioselective addition of organometallics to unprotected carboxylic acids

Nature Communications
Xingchen Yan, Syuzanna R Harutyunyan

Abstract

Conjugate addition of organometallics to carbonyl based Michael acceptors is a widely used method that allows the building of new carbon-carbon (C-C) bonds and the introduction of chirality in a single step. However, conjugate additions to the simplest Michael acceptors, namely unprotected, unsaturated carboxylic acids, are considered to be prohibited by the fact that acid-base reactions overpower any other type of reactivity, including nucleophilic addition. Here we describe a transient protecting group strategy that allows efficient catalytic asymmetric additions of organomagnesium reagents to unprotected α,β-unsaturated carboxylic acids. This unorthodox pathway is achieved by preventing the formation of unreactive carboxylate salts by means of a reactive intermediate, allowing modifications of the carbon chain to proceed unhindered, while the stereochemistry is controlled with a chiral copper catalyst. A wide variety of β-chiral carboxylic acids, obtained with excellent enantioselectivities and yields, can be further transformed into valuable molecules through for instance catalytic decarboxylative cross-coupling reactions.

References

Mar 7, 2007·Angewandte Chemie·Xianfeng SunXumu Zhang
Oct 20, 2007·Proceedings of the National Academy of Sciences of the United States of America·Virginie NahoumWilliam Bourguet
Mar 22, 2008·Angewandte Chemie·Lukas J GoossenKäthe Goossen
Aug 14, 2008·Chemical Reviews·Syuzanna R HarutyunyanBen L Feringa
Feb 1, 2013·ACS Catalysis·Sakunchai Khumsubdee, Kevin Burgess
Nov 19, 2014·Angewandte Chemie·Jiawei RongSyuzanna R Harutyunyan
Jul 30, 2015·Journal of the American Chemical Society·Qiaozhi YanGuofu Zi
Sep 4, 2015·Journal of Medicinal Chemistry·Nikolaos EleftheriadisFrank J Dekker
Sep 14, 2017·Journal of the American Chemical Society·Won Jun JangJaesook Yun
Sep 30, 2017·Journal of the American Chemical Society·Mamen Rodríguez-FernándezSyuzanna R Harutyunyan
Dec 29, 2017·Journal of the American Chemical Society·Yujing ZhouStephen L Buchwald
Feb 13, 2019·Angewandte Chemie·Yucheng MuAmir H Hoveyda

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Citations

Sep 23, 2020·Chemistry : a European Journal·Luo GeSyuzanna R Harutyunyan
Nov 24, 2020·Angewandte Chemie·Won Jun JangJaesook Yun
Sep 23, 2020·Chemistry : a European Journal·Kirill KulishSyuzanna R Harutyunyan
Jul 7, 2020·Organic Letters·Achim LinkStephen L Buchwald
Nov 11, 2020·Journal of the American Chemical Society·Xingchen YanSyuzanna R Harutyunyan

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Methods Mentioned

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